Structure-Activity Relationships of Noncovalent Immunoproteasome β5i-Selective Dipeptides

J Med Chem. 2020 Nov 12;63(21):13103-13123. doi: 10.1021/acs.jmedchem.0c01520. Epub 2020 Oct 23.

Abstract

The immunoproteasome (i-20S) has emerged as a therapeutic target for autoimmune and inflammatory disorders and hematological malignancies. Inhibition of the chymotryptic β5i subunit of i-20S inhibits T cell activation, B cell proliferation, and dendritic cell differentiation in vitro and suppresses immune responses in animal models of autoimmune disorders and allograft rejection. However, cytotoxicity to immune cells has accompanied the use of covalently reactive β5i inhibitors, whose activity against the constitutive proteasome (c-20S) is cumulative with the time of exposure. Herein, we report a structure-activity relationship study of a class of noncovalent proteasome inhibitors with picomolar potencies and 1000-fold selectivity for i-20S over c-20S. Furthermore, these inhibitors are specific for β5i over the other five active subunits of i-20S and c-20S, providing useful tools to study the functions of β5i in immune responses. The potency of these compounds in inhibiting human T cell activation suggests that they may have therapeutic potential.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Proliferation / drug effects
  • Dipeptides / chemistry*
  • Dipeptides / metabolism
  • Dipeptides / pharmacology
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Lymphocyte Activation / drug effects
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemistry*
  • Proteasome Inhibitors / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Binding
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / metabolism
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism

Substances

  • Dipeptides
  • Proteasome Inhibitors
  • Protein Subunits
  • Proteasome Endopeptidase Complex